Enhanced cancer detection through probe modification

ABSTRACT

Body-mountable devices are provided to detect the presence or status of a tumor in a body by detecting one or more properties of a probe located in subsurface vasculature of the body. A wearable body-mountable device can be worn for a protracted period of time to detect a probe in the vasculature at low concentrations and/or at low rates. A body-mountable device can detect properties of the probe that are indicative of whether the probe has interacted with a tumor of the body and determine the presence or status of a tumor in the body based on such detected properties. Additionally or alternatively, the probe could be introduced into the body as a probe aggregate and released from if the probe aggregate is absorbed by a tumor. The presence of released probes could be detected to determine a presence or status of a tumor in the body.

BACKGROUND

Unless otherwise indicated herein, the materials described in thissection are not prior art to the claims in this application and are notadmitted to be prior art by inclusion in this section.

A number of scientific methods have been developed to detect, measure,and/or affect one or more analytes in a biological or other environment(e.g., a person's body). The one or more analytes could be any analytesthat, when present in or absent from a person's body, or present at aparticular concentration or range of concentrations, may be indicativeof a medical condition or health state of the person. The one or moreanalytes could be substances whose distribution, action, or otherproperties, interactions, or activities throughout an animal's body isof scientific or medical interest. The one or more analytes couldinclude pharmaceuticals or other substances introduced into thebiological or other environment to effect some chemical or biologicalprocess, or to be affected by such a chemical or biological process. Theone or more analytes could be present in living or nonliving human oranimal tissue, and could be detected, measured, or affected in an invivo, ex vivo, in vitro, or some other type of sample. The one or moreanalytes could include probes introduced into a body in order to providecontrast or to otherwise enable the detection of an analyte or physicalvariable in the body.

SUMMARY

Some embodiments of the present disclosure provide a body-mountabledevice including: (i) a sensor that is configured to be mounted to anexternal body surface of a body proximate a portion of subsurfacevasculature and that is configured to detect a probe in the portion ofsubsurface vasculature, wherein the probe has a property indicative ofwhether the probe has interacted with a tumor of the body; and (ii) acontroller that is operably coupled to the sensor and that includes acomputing device programmed to perform controller operations. Thecontroller operations include: (1) operating the sensor to detect theprobe and to measure the property indicative of whether the probe hasinteracted with a tumor of the body; and (2) determining whether a tumoris present in the body based on the measured property.

Some embodiments of the present disclosure provide a body-mountabledevice including: (i) a sensor that is configured to be mounted to anexternal body surface of a body proximate a portion of subsurfacevasculature and that is configured to detect a probe in the portion ofsubsurface vasculature, wherein the probe is configured to be releasedby a tumor of the body after a probe aggregate has been introduced intothe body and absorbed by the tumor, wherein the probe aggregatecomprises multiple instances of the probe linked together; and (ii) acontroller that is operably coupled to the sensor and that includes acomputing device programmed to perform controller operations. Thecontroller operations include: (1) operating the sensor to detect theprobe by measuring an amount of the probe in the portion of subsurfacevasculature; and (2) determining whether a tumor is present in the bodybased on the measured amount of the probe in the portion of subsurface.

Some embodiments of the present disclosure provide a method including:(i) introducing a probe into a body; (ii) mounting a body-mountabledevice to an external body surface of the body such that a sensor of thebody-mountable device is proximate a portion of subsurface vasculatureof the body, wherein the sensor is configured to detect a property ofthe probe in the portion of subsurface vasculature; (iii) detecting,using the sensor of the body-mountable device, a property of the probein the portion of subsurface vasculature; and (iv) determining whether atumor is present in the body based on the detected property of the probein the portion of subsurface vasculature.

These as well as other aspects, advantages, and alternatives, willbecome apparent to those of ordinary skill in the art by reading thefollowing detailed description, with reference where appropriate to theaccompanying drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic diagram of a human body, showing movement withinthe body of a probe that has been introduced into the body, inaccordance with an example embodiment.

FIG. 2A is an illustration of a probe leaving a portion of vasculatureand entering a tumor, in accordance with an example embodiment.

FIG. 2B is an illustration of the probe of FIG. 2A interacting with thetumor and leaving the tumor and entering the portion of vasculature, inaccordance with an example embodiment.

FIG. 3A is an illustration of a probe leaving a portion of vasculatureand entering a tumor, in accordance with an example embodiment.

FIG. 3B is an illustration of the probe of FIG. 3A interacting with thetumor and leaving the tumor and entering the portion of vasculature, inaccordance with an example embodiment.

FIG. 4A is an illustration of a probe leaving a portion of vasculatureand binding to a cell of a tumor, in accordance with an exampleembodiment.

FIG. 4B is an illustration of the probe of FIG. 4A leaving the tumorwhile associated with a cell of the tumor and entering the portion ofvasculature, in accordance with an example embodiment.

FIG. 5 is a schematic diagram of elements of a probe, in accordance withan example embodiment.

FIG. 6A is a schematic diagram of elements of a probe, in accordancewith an example embodiment.

FIG. 6B is a schematic diagram of the elements of the probe of FIG. 6Aafter interacting with a tumor, in accordance with an exampleembodiment.

FIG. 7A is a schematic diagram of elements of a probe, in accordancewith an example embodiment.

FIG. 7B is a schematic diagram of the elements of the probe of FIG. 7Aafter interacting with a tumor, in accordance with an exampleembodiment.

FIG. 8 is a side cross-sectional view of probes in a portion ofsubsurface vasculature and a device positioned proximate to the portionof subsurface vasculature, in accordance with an example embodiment.

FIG. 9 is a side cross-sectional view of nanoparticles in a portion ofsubsurface vasculature and a device positioned proximate to the portionof subsurface vasculature during a first period of time, in accordancewith an example embodiment.

FIG. 10 is perspective view of an example device.

FIG. 11 is an illustration of a number of body-mountable devices incommunication with a server, in accordance with an example embodiment.

FIG. 12 is a block diagram of an example device.

FIG. 13 is a flowchart of an example method.

DETAILED DESCRIPTION

In the following detailed description, reference is made to theaccompanying figures, which form a part hereof. In the figures, similarsymbols typically identify similar components, unless context dictatesotherwise. The illustrative embodiments described in the detaileddescription, figures, and claims are not meant to be limiting. Otherembodiments may be utilized, and other changes may be made, withoutdeparting from the scope of the subject matter presented herein. It willbe readily understood that the aspects of the present disclosure, asgenerally described herein, and illustrated in the figures, can bearranged, substituted, combined, separated, and designed in a widevariety of different configurations, all of which are explicitlycontemplated herein.

I. OVERVIEW

It can be beneficial to detect the presence, status, location, or otherproperties of cancerous tumors in a human body. A course of treatment(e.g., a chemotherapeutic regimen, a surgical intervention) can bedetermined based on a detected presence, location, status (e.g., size,stage of cancer, type of cancer, degree or rate of metastasis), or otherdetected properties of a tumor.

However, detection of such properties of a tumor can be difficult. Thisdifficulty can be related to the location of a tumor within deep tissuesof the body, making detection (e.g., through fluorescence imaging, X-rayimaging, magnetic resonance (MR) imaging, or other imaging modalities)difficult due in part to the presence of intervening tissues between thetissue and any devices used to image the tumor. Alternatively,properties of the tumor could be detected based on properties ofcirculating tumor cells (CTCs) emitted into the circulation by thetumor. However, such detection can be difficult due to the rarity ofsuch CTCs in the blood.

In order to detect properties of a tumor, a probe that is configured tobe altered by or to otherwise interact with the tumor can be introducedinto the body (e.g., via intravenous injection). Such a probe could thentravel, via the circulatory system of the body, to a location near anexternal surface of the body (e.g., to a portion of subsurfacevasculature). Once proximate to the surface of the body, the probe couldbe detected by a body-mountable device. The body-mountable device couldoperate to detect one or more properties of the probe that are relatedto the tumor (e.g., to properties of the tumor, to the interactionbetween the probe and the tumor) and such detected properties could beused to determine a presence or status of the tumor.

Such a body-mountable device could be configured to be mounted to anexternal body surface (e.g., a skin surface) such that a sensor of thebody-mountable device is located proximate a portion of subsurfacevasculature beneath the external body surface. The sensor could thendetect the presence or other properties of the probe in the portion ofsubsurface vasculature. Such a body-mountable device could include ahand-held or desktop device that could be mounted to a skin surface byplacing the device in contact with the skin surface and/or by moving anarm or other body part to contact the device. Additionally oralternatively, the body-mountable device could be a wearable device(e.g., a wrist-mountable wearable device) that could be worn on a bodysurface. Such a wearable body-mountable device could operate, over aprotracted period of time, to detect the probe. Such protractedoperation could provide for the detection of rare events (e.g., aninfrequent release of the probe from the tumor) and/or the detection ofchanges in properties of a tumor over the protracted period of time

The probe could have a property that is related to exposure of the probeto a tumor. For example, the probe could have a fluorescence intensitythat increases or decreases as a result of exposure to the tumor.Additionally or alternatively, the probe could be introduced into thebody as part of an aggregate that can be absorbed by the tumor. Releaseof the probe from the aggregate could be dependent upon exposure to thetumor (that is, if the aggregate is absorbed into non-tumor tissue, theprobe is not released from the aggregate). In such examples, detectionof the probe in the portion of subsurface vasculature could beindicative of the presence or status of the tumor.

The probe could be configured to change a property, to be released froman aggregate, or to be otherwise modified in response to exposure to avariety of factors present in a tumor. In some examples, a pH, an oxygencontent, an amount of lactic acid, the presence of a tumor-specificprotease, or some other aspect of the environment within the tumor couldcause modification and/or release of a probe present in the tumor. Suchfactors could effect modification and/or release of a probe by a varietyof processes. For instance, such factors could cause a portion of theprobe to be cleaved off (e.g., a quencher to be cleaved off of theprobe) and/or could cause the probe to be released from an aggregate orother anchoring substance. In some examples, such factors could cause adenaturation, a change in conformation, or some other change in thestructure or geometry of the probe (e.g., such that the distance betweena quencher and a fluorophore is increased). In further examples, acoating or other substance of the probe could be dissolved by factorspresent in the tumor.

The probe could have a variety of properties that could be detected by abody-mountable device when the probe is located within a portion ofsubsurface vasculature. Such properties could be used to detect thepresence of the probe and/or such properties could be related to theexposure of the probe to a tumor environment. In some examples, theprobe could include a fluorophore, a Raman dye, or some other opticallyactive material having a fluorescence intensity, an excitation spectrum,an emission spectrum, an absorption spectrum, a color, or some otheroptical property that could be detected. Additionally or alternatively,the probe could include magnetic material (e.g., a magnetic chemicalmoiety, a nanoparticle of superparamagnetic iron) and a coercivity, asusceptibility, an intrinsic or induced magnetic field, a hysteresiscurve, a magnetic resonance, or some other magnetic property of theprobe could be detected. The probe could include multiple suchdetectable elements.

The presence or status of a tumor can be detected, based on detectedproperties of the probe in a portion of subsurface vasculature, in avariety of ways. If the probe is absorbed into the tumor or othertissues and is released substantially only from the tumor (e.g., due tothe probe being associated with tumor cells and being released with thetumor cells when they metastasize, or the probe being released from anaggregate or other anchor as a result of exposure to the tumorenvironment), detection of the probe in the portion of subsurfacevasculature can indicate the presence of the tumor, a size of the tumor,a type of the tumor, a rate of metastasis or the tumor, or some otherstatus information about the tumor. If the probe has a property that isrelated to exposure to the tumor (e.g., a fluorescence intensity that isincreased by exposure to the tumor), the presence, size, type, or someother status information about the tumor can be determined based on thedetected property.

Those of skill in the art will understand a “probe” in its broadestsense and that it may take the form of any fabricated material, amolecule, cryptophane, a virus, a phage, etc. or some combinationthereof. In practice, a plurality of probes will be administered to abody, and one or more of the administered probes can then be detected,in a portion of subsurface vasculature, by a body-mountable devicemounted proximate the portion of subsurface vasculature or by some otherdevice disposed on or within the body. The probe can include one or moredetectable elements, e.g., fluorophores, Raman dyes, dyes, magneticnanoparticles, quantum dots, fluorescent nanodiamonds, or other elementsthat can be detected by magnetic, optical, or other methods. The probecan be configured to selectively bind to one or more analytes (e.g.,chemicals, hormones, peptides, DNA or RNA fragments, cells), forinstance, to bind to tumor cells and/or to be incorporated within suchcells. The probe could include one or more elements configured to becleaved, to be denatured, to change a conformation, or to be otherwisemodified by exposure to one or more conditions in the environment of atumor, e.g., to a pH level, a concentration of lactic acid, an oxygenlevel, a concentration of one or more cancer-type-specific proteases, orsome other conditions present in a tumor.

It should be understood that the above embodiments, and otherembodiments described herein, are provided for explanatory purposes, andare not intended to be limiting.

Further, the term “tumor” as used herein should be understood broadly toinclude any mass of abnormal tissue growth within a body, e.g., aneoplasm. A tumor as described herein could be a benign tumor or amalignant tumor. A tumor could be a primary tumor (e.g., a mass of cellsat the anatomical site of an original tumor cell) or a secondary tumor(e.g., a mass of cells grown from one or more cells that metastasizedfrom an original tumor. A tumor could be formed from brain cancer cells,breast cancer cells, skin cancer cells, colon cancer cells, esophagealcancer cells, pancreatic cancer cells, or some other type of cancercells. Accordingly, the environment within a tumor could have a pH, adistribution of proteases, proteins, or other analytes, a temperature,an oxygen content, or some other properties that are related to the typeof cells present in the tumor and/or on the structure of the tumor.

II. DOWNSTREAM DETECTION OF TUMOR PROPERTIES USING EXOGENOUS PROBES

As noted above, it can be difficult to detect the presence, status, orother information about a tumor located within a body. Imaging contrastagents (e.g., X-ray contrast agents, MR contrast agents) can be used toimage a tumor, but such imaging may involve the use of large, expensiveimaging equipment (e.g., CT scanners, MR imagers), limiting thefrequency and convenience of such options. Conversely, exosomes,circulating tumor cells (CTCs), or other analytes emitted from the tumorcould be detected in the bloodstream (e.g., in a sample of blood drawnfrom the body), but such analytes can be rare and difficult tospecifically detect.

As an alternative, a probe that is configured to travel through thecirculation to a tumor could be introduced into the body (e.g., byintravenous injection). The probe could then interact with the tumor insome way, and subsequently leave the tumor to re-enter the circulation.Such probes could then be detected when they travel through theperipheral circulation (e.g., through a portion of subsurfacevasculature that is easily visible through the skin by a body-mountabledevice) and the presence or status of the tumor could be determinedbased on the detection of the probes and/or the detection of one or moreproperties of the probes.

As an illustrative example, FIG. 1 shows the motion of a probe through ahuman body 100. The body 100 includes a tumor 101. The probe is injectedinto the bloodstream of the body 100 by a syringe. The heart 103 of thebody 100 pumps blood through the vasculature of the body; as a result,the injected probe travels 111 from the site of the injection to theheart 103. The probe can then travel to a variety of locations in thebody, and may circulate multiple times through the heart 103 beforeexiting the circulation and/or being destroyed or disabled.

In a first example path 114, the probe circulates through thevasculature without interacting with the tumor 101 and eventually passesthrough a portion of subsurface vasculature 120 proximate to which abody-mountable device 130 is mounted. A sensor 135 of the body-mountabledevice 130 could detect the probe, e.g., could detect the presence ofthe probe in the portion of subsurface vasculature 120 and/or coulddetect some property of the probe (e.g., a fluorescence intensity) thatis related to whether the probe has been exposed to the tumor 101. In asecond example path 112, some of the probes that have not interactedwith the tumor 101 are removed from the circulation. This could includebeing falling out of the circulation into non-tumor tissues, beingdamaged or destroyed by the environment of the body, being eliminated aswaste (e.g., by the kidneys or liver), or being otherwise eliminated ordeactivated. A third example path 113 shows some of the introducedprobes leaving the circulation and entering the tumor 101.

The introduced probes could preferentially enter the tumor 101 (ratherthan being recirculated through the vasculature, being deposited inother tissues, or being eliminated via the kidneys) due, in part, to theenhanced permeability and retention (EPR) effect of the tumor 101. TheEPR effect is a property of many tumor types by which certain contentsof the blood (e.g., liposomes, nanoparticles, macromolecular drugs)accumulate within a tumor. This effect can be related to the vasculaturewithin the tumor being fenestrated (e.g., having more holes thanvasculature in other tissue) or otherwise formed differently fromvasculature in other tissues (e.g., by lacking a smooth muscle layer orby exhibiting some other modified properties). The EPR effect canadditionally or alternatively be related to a decreased amount oflymphatic drainage from tumor tissues relative to other tissues. Theprobe and/or an aggregate or other substance that includes the probecould have a size, geometry, or other properties specified based onproperties of the EPR effect to increase the likelihood of the probeleaving the vasculature to enter the tumor 101.

Such probes that enter the tumor 101 could then exit the tumor (shown asexample path 115). In some examples, probes could exit the tumor as aresult of being released from an aggregate or other anchoring substance.Additionally or alternatively, a probe could be associated with (e.g.,bound to, disposed within) a tumor cell and the probe could exit thetumor 101 as a result of the tumor cell metastasizing from the tumor101. As illustrated by example path 116, some of the probes that haveinteracted with and exited the tumor 101 will leave the bloodstream(e.g., via the kidneys or liver, or by deposition in tissues of thebody) and/or be damaged or destroyed by the body (e.g., by the action ofthe immune system of the body and/or by exposure to the pH or otherfactors of the blood). Alternatively, some of the probes that exit thetumor 101 could travel (as shown by example path 117) to the portion ofsubsurface vasculature 120 to be detected by the sensor 135 of thebody-mountable device 130. The presence or status (e.g., type, size,stage, rate or degree of metastasis) of the tumor 101 could then bedetermined based on the detection of such probes.

As illustrated in FIG. 1, the probe is introduced into the body 100using a hypodermic syringe 110. However, the probe could be introducedinto the bloodstream in a variety of other ways. For example, the probecould be introduced via a catheter, intravenous port, a transdermalpatch or other transdermal delivery means, or other means for accessingthe vasculature. Additionally or alternatively, the probe could beadministered orally (e.g., in a pill or other ingestible substance) andcould be absorbed by the body into the bloodstream.

As illustrated in FIG. 1, the body-mountable device 130 is mounted to awrist of the body 100 in order to detect probes that may be present inthe portion of subsurface vasculature 120 located beneath skin of thewrist. The body-mountable device 130 could be configured to be mountedto a skin surface proximate some other portion of subsurfacevasculature, e.g., an ankle, an arm a leg, a location on the torso, orsome other location where probes in subsurface vasculature can bedetected, e.g., by detecting a magnetic field, an electromagnetic field,a light, or some other energy or field produced by the probe. Further,as noted above, some of the probes detected in such a portion ofsubsurface vasculature by such a body-mountable device could includeprobes that have not been released from, passed through, been modifiedby, or otherwise interacted with a tumor (e.g., 101).

The sensor 135 could detect a variety of physical variables in order todetect a probe in the portion of subsurface vasculature 120. In someexamples, the sensor 135 could be configured to detect an intensity, aspectrum, a color, or some other property of light reflected, refracted,fluorescently absorbed and re-emitted, scattered, or otherwise emittedby the probe (e.g., by a fluorophore, chromophore, Raman dye,fluorescent nanodiamond, or other element of the probe). Additionally oralternatively, the sensor 135 could directly or indirectly detect amagnetic field produced by the probe (e.g., by a nanoparticle ofsuperparamagnetic iron or other magnetic element of the probe). Thesensor 135 could detect some other physical variable that is related tothe presence of the probe in the portion of subsurface vasculature 120proximate the sensor 135 and/or that is related to a property of theprobe that is indicative of whether the probe has interacted with thetumor 101. Based on such detected physical variables, the presence,number, location, or other properties of probes in the portion ofsubsurface vasculature 120 could be determined. Further, in someexamples, such detected physical variables could be used to determinewhether a particular probe has interacted with a tumor, to determine howlong the probe interacted with the tumor, to determine a property of thetumor (e.g., a pH level in the tumor, a tumor type), or to determinesome other information.

The presence or status of the tumor 101 could be determined based on thedetection of the probe and/or the detection of one or more properties ofthe probe. For example, the presence, size, type, rate of metastasis,stage, or other status information of the tumor 101 could be determinedbased on a rate at which the probe is detected in the portion ofsubsurface vasculature 120, a number of individual probes detected, orsome other information about the rate or amount of the probe that isdetected using the sensor 135. Additionally or alternatively, inexamples wherein the probe has a property that is indicative of whetherthe probe has interacted with the tumor, such information about thetumor 101 could be determined based on the detected property of theprobe. Such determinations could also be based on information about theintroduction of the probe into the body 100, e.g., based on a timing orrate of introduction of the probe into the body 100 or based on anamount of the probe that is introduced into the body 100.

As noted above, there could be a protracted period of time (e.g., hours,weeks, months) between introduction of a probe into the body 100,absorption of the probes into the tumor 101 and/or interaction betweenthe probe and the tumor 101, and release of the probes from the tumor101 into the circulation such that the probe can travel to the portionof subsurface vasculature 120. The probe could be configured to bedetectable (e.g., to have fluorophores, magnetic elements, or otherdetectable elements) over such extended periods of exposure toconditions within the body.

For example, the probe could include elements that are intrinsicallystable within the body, e.g., resistant to chemical reaction, immuneattack, dissolution, photobleaching, or other damaging processes withinthe body. Such intrinsically stable elements could include fluorescentnanodiamonds, particles of superparamagnetic iron or other magneticmaterials, or quantum dots or rods or other fluorescent and/or plasmonicmaterials formed from semiconductors or from other materials that aresubstantially stable over extended periods of time when exposed toenvironments within the human body. Such stability could be related toexposure to the tumor environment, such that the detectable element ismore stable within the tumor environment (where it may remain for aprotracted period of time) and less stable when out of the tumorenvironment (e.g., within the portion of subsurface vasculature 120).For instance, the detectable element could be a pH-sensitive fluorophoreand exposure of the fluorophore to the environment within the tumor(e.g., to a pH level characteristic of the tumor environment) couldreduce a rate of photobleaching of the fluorophore (e.g., by changing anexcitation or emission spectrum of the fluorophore and/or by quenchingthe fluorophore).

Additionally or alternatively, the probe could include protectivestructures to protect elements of the probe from damaging processeswithin the human body. For example, a fluorophore, magneticnanoparticle, or other detectable element or material could be coatedwith or otherwise enclosed within a protective material, e.g., within ananoparticle of polystyrene. In other examples, fluorophores or otherdetectable elements could be enclosed within liposomes or micelles forprotection.

In examples in which the probe remains in the tumor 101 for a protractedperiod of time, the probe could be introduced into the body 100 in smallamounts over an extended period of time. Introduction of a probe insmall amounts could reduce undesirable effects on the kidneys, liver, orother body systems when compared to introduction of the probe in largeramounts. In one approach, the probe is configured to tag tumor cellsbefore the cells enter the circulation, so as to allow subsequentdetection of the tumor cells in circulation (as CTCs) by thebody-mountable device 130 detecting the probe in the portion ofsubsurface vasculature 120. Smaller amounts of the probe can beadministered to detect such CTCs than if the probe is configured toassociate with the tumor cells after the cells have entered circulation.This lowered amount could be related to the rarity of such CTCs in thecirculation at any particular point in time and/or to the lowconcentration of such CTCs in the circulation.

As noted above, probes as described herein could travel through thevasculature of a body to a tumor, interact with the tumor, and bedetected downstream in a portion of subsurface vasculature by abody-mountable device. Based on the detected probe, a presence or status(e.g., size of the tumor, degree or rate of metastasis of the tumor,type of the tumor) of the tumor could then be determined. In someexamples, the probe is configured to bind specifically to cells of thetumor, to re-enter the circulation from the tumor and not from othertissues, or to otherwise be present in the circulation in an amount thatis related to the presence or status of the tumor; in such examples,detection of the probe in a portion of subsurface vasculature could beused to infer the presence or status of the tumor. Additionally oralternatively, the probe could have a property (e.g., a fluorescenceintensity) that changes in response to interaction between the probe andthe tumor (e.g., in response to exposure of the probe to the tumorenvironment); in such examples, such a detected property indicative ofwhether the probe has interacted with the tumor could be used to inferthe presence or status of the tumor.

In some examples, a probe could be absorbed into tissues along with anaggregate (e.g., an aggregate of multiple instances of the probe) orother anchoring substance. If the probe (and associated aggregate orother anchoring substance) is absorbed into a tumor, the probe could beresponsively released from the tumor into the bloodstream. Such areleased probe could be detected downstream (e.g., in a portion ofsubsurface vasculature by a body-mountable device mounted proximatethereto) and used to determine the presence or status of the tumor. Asan illustrative example, FIG. 2A shows a tumor 220 within a body and aportion of vasculature 210 proximate the tumor 220. Blood flows into 221a and out of 211 b the portion of vasculature 210. The portion ofvasculature 210 is fenestrated (i.e., has breaks in its walls); as aresult, cells, macromolecules, probes, or other contents of the bloodflowing into 221 a the portion of vasculature 210 can leave the portionof vasculature 210 and interact with the tumor 210. For instance, and asillustrated in FIG. 2A, a probe aggregate 200 that includes a probe 230attached to an anchoring element 240 via a linking element 245 has leftthe portion of vasculature 210 and been absorbed by the tumor 220.

The probe aggregate 200, linking element 245, probe 230, and/or theanchoring element 240 could include a variety of compounds orstructures. Further, while a single probe 230 is illustrated as beingattached to the anchoring element 240, more than one probe could beattached to a single anchoring element and/or the anchoring element 240could itself comprise a number of probes. The anchoring element 240could comprise a variety of substances configured to be absorbed into atumor from the bloodstream. For instance, the anchoring element 240could be a nanoworm composed of a plurality of nanoparticles of ironoxide that are coated in polyethylene glycol, dextran, or some othercoating material. The anchoring element 240 could include elementsconfigured to selectively bind to tumor cells (e.g., an aptamer, anantibody, a tumor-targeting peptide) to improve the targeting of theprobe aggregate 200 to the tumor 220.

The linking element 245 could bind a fluorophore, a magneticnanoparticle, a quantum dot, or other elements of the probe 230 to theanchoring element 240 until the probe aggregate 200 is absorbed into atumor (e.g., 220). After the probe aggregate 200 is absorbed into atumor, the linking element 240 could release the probe 230 back into thecirculation, such that the probe 230 may be detected in superficialvasculature by a body-mountable device. This is illustrated by way ofexample in FIG. 2B, wherein the linking element has released the probe230 from the anchoring element 245. This release could include thelinking element 245 being cleaved, lysed, or otherwise modified inresponse to one or more factors (e.g., a pH level, an oxygenation level,a concentration and/or presence of a tumor-specific protease) present inthe tumor 220. Also illustrated in FIG. 2B are other probe aggregatesand/or anchoring elements that have been absorbed into the tumor 220.

As illustrated in FIGS. 2A and 2B, a probe that has been absorbed into atumor can be released, from a probe aggregate that contains the probeand that has been absorbed into the tumor with the probe, in response toexposure of the probe and/or probe aggregate to tumor-specificproperties of the tumor environment. As a result, detection of suchreleased probes can provide information about the presence or status ofthe tumor. Additionally or alternatively, a probe could associate withcells of a tumor such that the probe remains associated with the tumorcells after the tumor cells metastasize from the tumor into thebloodstream.

As an illustrative example, FIG. 3A shows a tumor 320 within a body anda portion of vasculature 310 proximate the tumor 320. The tumor 320 iscomprised of a plurality of tumor cells, including a particular tumorcell 340. Blood flows into 321 a and out of 311 b the portion ofvasculature 310. The portion of vasculature 310 is fenestrated (i.e.,has breaks in its walls); as a result, cells, macromolecules, probes, orother contents of the blood flowing into 321 a the portion ofvasculature 310 can leave the portion of vasculature 310 and interactwith the tumor 310. For instance, and as illustrated in FIG. 3A, a probe300 has left the portion of vasculature 310 and associated with theparticular tumor cell 340.

As illustrated in FIG. 3A, the probe 300 associating with the tumor cell340 includes the cell binding to the outside of the tumor cell 340. Suchbinding could be facilitated by the probe 300 including elementsconfigured to selectively bind to the outside of tumor cells (e.g., theprobe 300 could include an aptamer, an antibody, a tumor-targetingpeptide). Alternatively, the probe 300 could associate with a tumor cellby entering the tumor cell, e.g., by including recognition proteins orother elements configured to induce endocytosis of the probe 300 by atumor cell. Further, the association of the probe 300 with a cell (e.g.,a tumor cell) could be dependent upon one or more factors (e.g., a pHlevel, an oxygenation level, a concentration and/or presence of atumor-specific protease) present in the tumor 320 in order to increasethe specificity of association of the probe 300 with cells of the tumor320. For example, an element of the probe that is configured to bind toor otherwise interact with tumor cells (e.g., an antibody, a receptor,an aptamer) could have a conformation that is dependent on pH such thatthe element only acts to bind to or otherwise interact with tumor cellswhen exposed to a pH that is typical of the environment within a tumor.In another example, an element of the probe could be configured tointerfere with such a receptor or other binding agent of the probe(e.g., the probe could include a competitive agonist that is configuredto bind to a receptor and that is tethered to the probe). Such aninterfering element could be cleaved off or otherwise disabled due toexposure to a tumor environment (e.g., in response to a protease that istypically present in a tumor). In yet another example, the probe 300could include a protective layer that is selectively degraded byexposure to the tumor environment (e.g., by a lowered pH characteristicof the tumor environment) and degradation and/or removal of theprotective layer could allow for association of the probe 300 with tumorcells (e.g., could reveal an aptamer, antibody, receptor, or otherelement(s) of the probe 300 configured to cause selective associationwith tumor cells and/or to cause association with cells in general).

The after the probe 300 is associated with a tumor cell (e.g., 340), theprobe 300 could move back into the circulation when the associated tumorcell metastasizes into the circulation. The probe 300 may then bedetected in superficial vasculature by a body-mountable device. This isillustrated by way of example in FIG. 3B, wherein the tumor cell 340 hasmetastasized into the portion of vasculature 310. As a result, detectionof the released probe 300 can provide information about the presence orstatus of the tumor, e.g., a rate or stage of metastasis or progressionof the tumor. Also illustrated in FIG. 3B are other probes that haveassociated with tumor cells in the tumor 320.

As noted above, a probe can additionally or alternatively have aproperty that is indicative of whether the probe has interacted with atumor of the body. For example, a fluorescence intensity of the probe,an excitation spectrum of the probe, an emission spectrum of the probe,a size of the probe, a presence or absence of one or more elements ofthe probe, a magnetic moment of the probe, or some other property of aprobe could be affected by interaction with a tumor. Such an interactioncould include the probe being exposed to the environment within a tumor(e.g., to a pH level or an oxygen level characteristic of a tumor), theprobe binding to tumor cells of the tumor, the probe catalyzing areaction of a substance within the tumor and/or a substance within thetumor catalyzing a reaction of one or more elements of the probe (e.g.,an element of the probe being cleaved, denatured, or otherwise alteredby a protease that is characteristically present in the tumor), or someother interaction. Such interactions could effect a change in theindicator property of the probe by a variety of mechanisms. For example,an element (e.g., a fluorescence quencher, a fluorophore, a magneticnanoparticle, a quantum dot) of the probe could be cleaved from theprobe, denatured, damaged, dissolved, disabled, could experience achange in conformation or geometry, or otherwise altered as a result ofinteraction with the tumor. Additionally or alternatively, one or moreelements could be added to the probe (e.g., a protein, an antibody, andantigen, a cell, a macromolecule) as a result of interaction with atumor.

A probe that has such a property indicative of whether the probe hasinteracted with a tumor of the body could interact with a probe that islocated within a body, travel in the circulation to a portion ofsubsurface vasculature, and be detected by a body-mountable deviceproximate to the portion of subsurface vasculature. The body-mountabledevice could detect the property of the probe and such a detectedproperty could be used to determine the presence or status of the tumor.As an illustrative example, FIG. 4A shows a tumor 420 within a body anda portion of vasculature 410 proximate the tumor 420. Blood flows into421 a and out of 411 b the portion of vasculature 410. The portion ofvasculature 410 is fenestrated (i.e., has breaks in its walls); as aresult, cells, macromolecules, probes, or other contents of the bloodflowing into 421 a the portion of vasculature 410 can leave the portionof vasculature 410 and interact with the tumor 410. For instance, and asillustrated in FIG. 4A, a probe 400 has left the portion of vasculature410 and entered the tumor 420.

As illustrated in FIG. 4A, the probe 400 includes a fluorophore 430 anda quencher 440 that is configured to quench the fluorescence of thefluorophore 430. After the probe 400 enters the tumor, the quencher 440could be prevented from quenching the fluorophore 430 and/or a degree ofquenching of the fluorophore 430 by the quencher 440 could be decreased.As a result, the fluorescence intensity of the fluorophore 430, and thusof the probe as a whole, could be increased, and such an increasedfluorescence intensity could be detected by a body-mountable device ifthe probe travels to a portion of superficial vasculature proximate sucha device. This is illustrated by way of example in FIG. 4B, wherein thequencher 440 has been cleaved from the probe 400. The probe 400 thenleaves the tumor and enters the portion of vasculature 410.

As noted above, a body-mountable device could detect the presence and/orone or more properties of a probe as described herein, and such adetected presence or property could be used to determine a presence orstatus of a tumor in a body. Such a determined presence or status (e.g.,a determined tumor type, size, stage, degree or rate of metastasis)could be used to determine a course of treatment. For example, a courseof chemotherapy, a surgical intervention, or some other treatments couldbe determined and executed in response to determining that a tumor ispresent and/or that such a tumor is of a certain type, is metastasizing,or has some other status. Additionally or alternatively, a tumor couldbe imaged (e.g., using an X-ray computerized tomography scanner, using amagnetic resonance imager, using a gamma camera, using a fluorescenceimager) in response to determining that the tumor is present using aprobe and body-mountable (or otherwise configured) device as describedherein. In such examples, the probe could function as a contrast for theimaging, e.g., the probe could include an X-ray contrast agent (e.g., aniodine or barium compound), an MR contrast agent (e.g., particles ofgadolinium), a positron emitter, a fluorophore, or some other contrastagent to facilitate imaging of the tumor.

As noted above, a probe could interact with a tumor in a variety of wayssuch that a property of the probe is changed, such that the probe isreleased from the tumor, or such that some other process occurs that canbe detected by a body-mountable device if the probe travels, through thecirculation, to a portion of subsurface vasculature that is observableby the body-mountable device. Such changes (e.g., cleavage of elementsof the probe, denaturation of elements of the probe, changes inconformation or geometry of the probe, addition of elements to theprobe, association of the probe with a tumor cell) could be caused byexposure to the environment of a tumor. For example, a pH level, anoxygen saturation, a concentration of lactic acid, a similarity betweenthe tumor environment and the blood (e.g., due to the tendency for thevasculature of a tumor to be fenestrated and/or due to the enhancedpermeability and retention effect), a presence or concentration of aprotease, protein, or other substance, or some other property of theenvironment of a tumor that is characteristic of the tumor. A probecould be sensitive to such factors that are common across a variety oftumor types (e.g., a decreased pH within a tumor relative to othertissues of a body) and/or to factors that are specific a particulartumor type or set of tumor types (e.g., the presence of a protease thatis characteristic of a particular variety of cancer).

In order to control the specificity of a probe to tumors and/or to aparticular tumor type, the probe could only change a property, associatewith cells, be released from a probe aggregate or other anchoringelement, or otherwise experience some change in response to exposure tomultiple factors that are characteristic of tumors and/or a particulartumor type. For instance, cleavage of the probe from an anchor and/orcleavage of some other element of a probe could be dependent on exposureto multiple factors (e.g., a pH within a specific range and a protease,or two different proteases). As an example, FIG. 5 illustrates first 510a and second 520 a elements of a probe 500 a. The first and secondelements 510 a, 520 a are connected by first 530 a and second 535 alinking elements (e.g., first and second peptides) that are configuredto be cleaved by respective different factors of a tumor environment(e.g., first and second different proteases that are both characteristicof a particular tumor type). The first and second elements 510 a, 520 acould be, respectively, a fluorophore and a quencher, a probe and ananchoring element, or some other combination of elements. The first andsecond elements 510 a, 520 a could be separated if the probe 500 a isexposed to both of the different factors such that the first 530 a andsecond 535 a linking elements are both cleaved. A probe could beconfigured to be sensitive to more than two factors, to cleave (or tochange in some other way) in response to the presence of at least one ofa set of factors (e.g., by assembling the first 530 a and second 535 alinking elements in series, rather than in parallel as shown in FIG. 5)or according to some other combination or permutation of factorsaccording to an application.

As noted above, first and second elements of a probe could be cleavedapart to release the probe, to change a property of the probe (e.g., bycleaving off a quencher, a fluorophore, or some other detectableelement). Alternatively, a property of a probe could be changed bychanging a conformation or geometry of elements of the probe, e.g., toincrease a distance between a quencher and a fluorophore to decrease adegree of quenching of the fluorophore by the quencher. As an example,FIG. 6A shows a probe 600 that includes a fluorophore 610 and a quencher620. A fluorescence intensity of the fluorophore 620 is related to thedistance between the fluorophore 610 and a quencher 620 such that thefluorescence intensity of the fluorophore 610 increases as the distanceto the quencher 620 increases.

Thus, exposure to a tumor environment, or some other interaction betweena tumor and the probe 600, could change (e.g., increase) thefluorescence intensity of the probe 600 by changing the distance (e.g.,increasing the distance) between the fluorophore 610 and the quencher620. This is illustrated by way of example in FIG. 6B, wherein the probe600 has changed its geometry such that the distance between thefluorophore 610 and the quencher 620 is increased relative to theconfiguration of the probe 600 that is shown in FIG. 6A. As a result,the fluorescence intensity of the fluorophore 610 (and thus of the probe600) is increased.

Such an increased (or decreased) distance between elements of a probecould be caused by changes in the structure of a protein or otherelements of the probe, e.g., the cleavage of a tether between elementsof the probe, a change in secondary or tertiary structure of a proteinof the probe, or some other change. Such changes in the structure of aprobe could be due to a substance (e.g., a protein, an antibody, anaptamer) that is present in a tumor binding to the probe (e.g., to causea change in conformation of an antibody or other elements of the probe),a reaction between the probe and a substance (e.g., a protease, anenzyme) that is present in the tumor such that the reaction denature,lyses, cleaves, or otherwise alters the structure of a protein or otherelement of the probe, or some other mechanism.

A probe as described herein could have multiple properties that areindicative of whether the probe has interacted with a tumor. Forexample, the probe could have a fluorescence intensity at a number ofdifferent wavelengths (e.g., corresponding to multiple differentfluorophores and/or quenchers of the probe) where the fluorescenceintensity at each wavelength has a value that is related to whether theprobe interacted with a tumor and/or whether the probe interacted with atumor of a particular type. For instance, a probe could include a firstfluorophore having a first fluorescence intensity that is changed inresponse to exposure to a pH level characteristic of the tumorenvironment of a variety or tumor types and a second fluorophore havinga second fluorescence intensity that is changed in response to exposureto a protease that is characteristic of the tumor environment of aparticular tumor type. In such an example, detection of the first andsecond fluorescence intensities (e.g., by illuminating the probe withlight at first and second wavelengths and/or detecting light emittedfrom the probe at first and second wavelengths) could allow fordetermination of whether a tumor is present in a body and/or whethersuch a tumor is of the particular type.

Further, a property of a probe that is indicative of whether the probehas interacted with a tumor could be related to some property of theinteraction and/or of the tumor such that the property of theinteraction and/or of the tumor could be determined based on thedetected property of the probe. For example, a degree of reduction orincrease of the fluorescence intensity of a probe from a baseline levelcould be related to the level of pH in a tumor, a size of the tumor, anamount of time the probe interacted with the tumor (e.g., an amount oftime between the probe being absorbed into or otherwise exposed to thetumor and the probe exiting the tumor), a degree of perfusion of thetumor, or some other property of the tumor and/or of the interaction ofthe probe with the tumor. The probe could be configured in a variety ofdifferent ways to provide such a property. For instance, the probe couldinclude a plurality of fluorophores that are configured to be cleavedoff of the probe or to otherwise exhibit a reduction in the overallfluorescence intensity of the probe as a result of interaction with theprobe (e.g., as a result of exposure to a protease in the tumor, or as aresult of exposure to a pH within the tumor). As the probe continuous tointeract with the tumor, the overall fluorescence intensity of the probecould decrease as more of the fluorophores are cleaved off or otherwisereduce their fluorescence intensity.

In order to determine whether a probe has interacted with a tumor, theprobe could have a first detectable property (e.g., a first fluorescenceintensity at a first excitation and/or emission wavelength) that isindicative of whether the probe has interacted with a tumor and a seconddetectable property (e.g., a second fluorescence intensity at a secondexcitation and/or emission wavelength, a magnetic field of a magneticnanoparticle) that is substantially independent of whether the probe hasinteracted with the tumor. The first and second properties could bedetected and used to determine whether the probe has interacted with atumor. Further, the detectable property that is substantiallyindependent of whether the probe has interacted with a tumor could beused to normalize the detectable property that is indicative of whetherthe probe has interacted with the tumor, e.g., to allow a duration oftime the probe interacted with the tumor, a pH level or other value of aproperty of the tumor, or some other property of the tumor and/or of theinteraction between the tumor and the probe to be determined.

As an illustrative example, FIG. 7A shows a probe 700 that includes afirst fluorophore 710 and a quencher 720. A first fluorescence intensityof the first fluorophore 710 is related to the distance between thefirst fluorophore 710 and a quencher 720 such that the firstfluorescence intensity of the first fluorophore 710 increases as thedistance to the quencher 720 increases. The probe 700 also includes asecond fluorophore 730 that has a second fluorescence intensity.Exposure to a tumor environment, or some other interaction between atumor and the probe 700, could increase the first fluorescence intensityof the probe 700 by increasing the distance between the firstfluorophore 710 and the quencher 720. This is illustrated by way ofexample in FIG. 6B, wherein the probe 700 has changed its geometry inresponse to interaction with a tumor such that the distance between thefirst fluorophore 710 and the quencher 720 is increased relative to theconfiguration of the probe 700 that is shown in FIG. 7A. As a result,the first fluorescence intensity of the first fluorophore 710 (and thusof the probe 700) is increased.

As shown in FIG. 7A, the probe 700 has not interacted with a tumor(e.g., has not been exposed to a pH, a protease, an oxygen content, orsome other factor characteristic of an environment of the tumor) and sothe first fluorescence intensity of the first fluorophore 710 is lowwhile the second fluorescence intensity of the second fluorophore 730 ishigh. A body-mountable device could detect the probe 700 as depicted inFIG. 7A in a portion of subsurface vasculature by detecting the lowfirst fluorescence intensity and high second fluorescence intensity; thedetected first and second fluorescence intensities could then be used todetermine that the probe 700 is present in the portion of subsurfacevasculature and that the probe 700 has not interacted with a tumor.Based on such a determination, a presence or status of a tumor in thebody could be determined.

Alternatively, as shown in FIG. 7B, the probe 700 has interacted with atumor (e.g., not been exposed to a pH, a protease, an oxygen content, orsome other factor characteristic of an environment of the tumor) and sothe first and second fluorescence intensities of the first fluorophore710 and second fluorophore 730, respectively, are high. A body-mountabledevice could detect the probe 700 as depicted in FIG. 7B in a portion ofsubsurface vasculature by detecting the high first and secondfluorescence intensities; the detected first and second fluorescenceintensities could then be used to determine that the probe 700 ispresent in the portion of subsurface vasculature and that the probe 700has interacted with a tumor. Based on such a determination, a presenceor status of a tumor in the body could be determined. Further, thesecond fluorescence intensity could be used to normalize the firstfluorescence intensity such that a property of the tumor (e.g., aconcentration of a protease, a pH level, a level of perfusion) and/or ofthe interaction between the probe 700 and the tumor (e.g., a duration oftime during which the probe was exposed to the tumor) could bedetermined based on the normalized first fluorescence intensity.

III. EXAMPLE DETECTION OF PROBES IN SUBSURFACE VASCULATURE

As noted above, a probe can be introduced into the vasculature of a bodyand travel to a tumor within the body. Such a probe could then interactwith the tumor and travel, via the vasculature, to a superficial portionof vasculature wherein the probe could be detected. The probeinteracting with a tumor could include being selectively released fromthe tumor, associating with tumor cells of the tumor and metastasizinginto the circulation with such cells, having a property that is alteredby exposure to the tumor and/or otherwise indicative of the probe havinginteracted with the tumor, or otherwise interacting with the tumor. Bytraveling via the circulation to a portion of subsurface vasculature,the probe can be detected over a protracted period of time by abody-mountable device (e.g., a wrist-mounted wearable device) that couldbe worn by a user and/or periodically (e.g., daily, for a period of afew minutes each day) mounted to a user's body (e.g., by placing the armof the user proximate the body-mountable device such that a sensor ofthe device is proximate a portion of subsurface vasculature of theuser's body) rather than less frequently by a CT scanner, an MRI device,or some other imaging or scanning equipment. Further, by interactingwith tumor cells in a tumor, the probe can leverage factors present inthe tumor microenvironment (e.g., a pH level, the enhanced permeabilityand retention effect) to increase the specificity of the probe.Additionally, such probes can be used to detect CTCs or other rare orinfrequent events or analytes in lower doses than might be required totag and detect such rare and/or infrequently present analytes directlyafter such analytes are present in the circulation.

As an illustrative example, FIG. 8 shows example probes 860 disposed ina blood vessel 850 (i.e., a portion of subsurface vasculature). In thisexample, disposed in blood vessel 850 are instances of the probe 860.The probes could be any type of probe as described elsewhere herein;further, multiple types of probe could be present in the blood vessel850. The blood vessel 850 is located in an arm 890 and contains bloodthat is flowing (direction of flow indicated by the arrow 855). Awearable body-mountable device 800 includes a housing 810 mountedoutside of or otherwise proximate to the blood vessel 850 by a mount 820configured to encircle the arm 890. The wearable device 800 includes asensor 830 (e.g., a light sensor, a light emitter, a magnetic sensor,and/or some other elements) that is configured to detect the probes 860in the blood vessel 850 that are proximate the sensor 830. Suchdetection can include detecting that the probe(s) 860 are present in theblood vessel 850, determining a number, concentration, or amount of theprobes 860 in the blood vessel 850 and/or determining properties of theprobes 860 in the blood vessel 850.

The sensor 830 could be configured to detect a variety of physicalproperties in order to detect the presence of the probes 860 and/or todetect one or more properties of individual probes 860 (e.g., a propertyof an individual probe that is indicative of whether the individualprobe has interacted with a tumor). This could include detectingphysical variables that are related to fluorophores, chromophores, dyes,Raman dyes, fluorescent nanodiamonds, fluorescent quantum dots, magneticnanoparticles, or other detectable elements of the probes 860. Thesensor 830 could be configured to detect such physical variables in sucha way that individual probes 860 can be detected. This could includedetecting the fluorescence intensity of a single probe and/or afluorophore of a single probe, detecting a magnetic field produced by amagnetic nanoparticle of a single probe, or detecting some otherdetectable element of a single probe 860 in the blood vessel 850.Additionally or alternatively, the sensor 830 could be configured todetect properties of a population of probes 860 in the blood vessel 850.This could include detecting the aggregate fluorescence intensity of apopulation of the probes 860 in the blood vessel 850, detecting a T1time, a T2* time, or some other magnetic resonance time constant ofhydrogen atoms in the blood that is related to magnetic fields producedby a population of magnetic nanoparticles of the probes, or detectingsome other aggregate property of probes 860 in the blood vessel 850.

In examples wherein the probes 860 have a detectable optical property(e.g., a color, an emission spectrum, an excitation spectrum, anabsorption spectrum, a Stokes shift), the sensor 830 could be configuredto detect such an optical property. The sensor 830 could include a lightsensor (e.g., a photodiode, a phototransistor, an avalanche photodiode,a CCD sensor, a camera, a spectrometer) that is configured to detect theintensity, polarization, wavelength, spectral content, degree ofcoherence, or other properties of light received from the blood vessel850, e.g., light emitted from probes 860 within the blood vessel 850.The sensor 830 could be configured to detect such properties of lightreceived from a relatively wide field of view encompassing a portion ofthe blood vessel 850 (e.g., to detect multiple probes 860) and/or couldinclude one or more sensing elements (e.g., pixels of a camera)configured to detect properties of light received from a sufficientlynarrow field of view that individual probes 860 and/or propertiesthereof could be detected. Further, the sensor 830 could include one ormore light emitters configured to illuminate the blood vessel 850, e.g.,to excite a fluorophore of the probes 860, to interrogate a color orabsorbance spectrum of the probes 860, or to interrogate some otheroptical property of the probes 860.

In examples wherein the probes 860 have a detectable magnetic property(e.g., a magnetic moment, a magnetic relaxation time, a coercivity), thesensor 830 could be configured to detect such a magnetic property. Thesensor 830 could include a Hall sensor, an atomic optical magnetometer,a multipass atomic magnetometer, a spin exchange relaxation-freemagnetometer, or some other element(s) configured to detect a magnitudeand/or direction of a magnetic field proximate the blood vessel 850. Thesensor 830 could detect a magnetic field produced by a magneticnanoparticle or other magnetic element of the probes 860 that ispermanently magnetized, that becomes magnetized spontaneously, or thathas been magnetized (e.g., by a permanent magnet or electromagnet of thewearable device 800). Additionally or alternatively, the wearable device800 could generate an alternating magnetic field and the sensor 830could detect the probes 860 by detecting magnetic fields produced by theprobes 860 in response to exposure to the alternating magnetic field(e.g., alternating magnetic fields at a harmonic frequency of thealternating field generated by the wearable device 800).

In some examples, the sensor 830 could indirectly detect a magneticfield produced by the probes 860, e.g., by detecting a change in themagnetic resonance properties of atoms in the blood. This could includepolarizing the magnetic spins of atoms in the blood (e.g., hydrogenatoms) using, e.g., a high-strength magnet or electromagnet of thewearable device 800, rotating the polarized atoms using coils of thewearable device 800 (e.g., emitting pi pulses, ½ pi pulses, or otherpulses or patterns of pulses used in nuclear magnetic resonance and/ormagnetic resonance imaging), and operating the sensor 830 to detectmagnetic fields produced by the atomic spins as they relax in a mannerrelated to magnetic fields produced by the probes 860.

A presence or status of a tumor in the body could be determined based ona detected presence and/or properties of probes 860 in the blood vessel850. Such a determination could be based on the properties of the probes860. For example, if the probes 860 are configured to be released from atumor subsequent to being absorbed into the tumor or to associate withtumor cells and to leave the tumor with associated tumor cells when thetumor cells metastasize, the presence of a tumor, a size of a tumor, atype of a tumor (e.g., if the probes 860 are configured to selectivelyassociate with and/or be released from a particular tumor type), a rateor degree of metastasis of a tumor, or some other information about thepresence or status of a tumor could be determined based on an amount ofdetected probes 860, a rate or frequency at which the probes 860 aredetected, and/or a timing of detection of the probes 860 relative to,e.g., introduction of the probes 860 into the body.

Additionally or alternatively, if the probes 860 have a property that isindicative of the probes having interacted with a tumor, the presence ofa tumor, a size of a tumor, a degree of perfusion of a tumor, a type ofa tumor (e.g., if the property of the probes 860 is indicative ofinteraction with a particular tumor type), a property of the environmentof a tumor (e.g., a pH level in the tumor), a property of theinteraction between a tumor and the probe(s) 860 (e.g., a duration oftime during which a probe was exposed to a tumor), or some otherinformation about the presence or status of a tumor could be determinedbased on a measured property of detected probes 860.

In some examples, probes as described herein could include magneticelements (e.g., nanoparticles of superparamagnetic iron oxide). As notedabove, magnetic fields produced by such magnetic elements could bedetected by a body-mountable device and used to determine the presenceor other properties of the probes in a portion of subsurface vasculatureand/or to determine the presence or status of a tumor in a body.Additionally or alternatively, such magnetic elements (e.g., magneticnanoparticles) could be used to collect probes in a portion ofsubsurface vasculature by exerting a magnetic force on the probes. Suchprobes could be collected to improve the detection of the presenceand/or other properties of the probes by, e.g., increasing a magnitudeof a magnetic field produced by the probes in the portion of subsurfacevasculature, by increasing the intensity of a light (e.g., afluorescence light) produced by the probes, or otherwise improving thedetection of some detectable property of the probes in the portion ofsubsurface vasculature by increasing the number or concentration of theprobes in the portion of subsurface vasculature.

FIG. 9 illustrates example probes 960 as described elsewhere herein. Theprobes 960 include magnetic nanoparticles and are disposed in a bloodvessel 950 (i.e., a portion of subsurface vasculature). The blood vessel950 is located in an arm 990 and contains blood that is flowing(direction of flow indicated by the arrow 955). A wearablebody-mountable device 900 includes a housing 910 mounted outside of theblood vessel 950 by a mount 920 configured to encircle the arm 990. Thewearable device 900 includes a sensor 930 disposed in the housing 910and configured to detect a detectable property of the probes 960 inorder to, e.g., determine the presence, location, or other properties ofthe probes 960. Such properties of the probes 960, detected using thesensor 930, could be used to determine a presence or status of a tumorin the body that comprises the arm 990.

The wearable device 900 additionally includes a magnetic flux source 935(e.g., a permanent magnet, an electromagnet) configured to exert anattractive magnetic force on the magnetic nanoparticles of the probes960 such that at least some of the probes 960 in the blood vessel 950are collected proximate the magnetic flux source 935. Such a magneticflux source could be considered a collection magnet. The magnetic fluxsource 935 could additionally be configured to magnetize the magneticnanoparticles of the probes 960, to polarize magnetic spins of nuclei(e.g., hydrogen nuclei) in the blood, or to provide some otherfunctions.

As shown in FIG. 9, the magnetic flux source 935 is exerting anattractive magnetic force to attract the probes 960 to form a bolus 975of collected probes 960. The sensor 930 could be configured to detectthe presence, amount, concentration, or other properties of the probes960 collected in the bolus 975 when the magnetic flux source 935 isexerting an attractive magnetic force on the probes 960. Additionally oralternatively, the magnetic flux source 935 could be configured and/oroperated to, after exerting a magnetic force sufficient to collect thebolus 975 of probes 960, exert a lesser magnetic force (e.g., to exertsubstantially no magnetic force) on the probes 960 such that the bolus975 is released from the proximity of the magnetic flux source 935 andflows within the blood vessel 950 to a downstream location, e.g., pastthe sensor 930. The sensor 930 could then operate to detect a lightemitted by the probes 960 (e.g., in response to illumination emittedfrom the sensor 930), a magnetic field produced by the probes 960 and/orsome other physical variable related to the probes 960.

IV. EXAMPLE BODY-MOUNTABLE DEVICES

Body-mountable devices as described herein can be configured to bemounted to an external body surface of a person and to enable a varietyof applications and functions including the detection of probes asdescribed elsewhere herein that are disposed in the body of the person(e.g., disposed in a portion of subsurface vasculature of the person)and that have a property (e.g., a fluorescence intensity, an amount ornumber of the probe that is present in a portion of vasculature, a rate,frequency, or timing of the probe being present in a portion ofvasculature) that is related to the presence or status of a tumor in thebody of the person. Such devices could include one or more sensorsconfigured to detect a light, a magnetic field, or some other physicalvariable that is related to the presence of one or more probes in aportion of subsurface vasculature proximate the sensor(s) and/or todetect a property (e.g., a fluorescence intensity, an emission spectrum)of such one or more probes.

In some examples, the probes could include magnetic nanoparticles andsuch devices could include one or more magnetic flux sources configuredto collect the probes in a portion of subsurface vasculature and/or toprovide some other functionality (e.g., to polarize the magnetic spinsof atomic nuclei in a body, to magnetize the magnetic nanoparticles).Such body-mountable devices could enable a variety of applications,including detecting properties of the probes in order to, e.g.,determine a presence or status of a tumor in the body of a person, todetect other physiological information about a person (e.g., heartrate), to indicate such determined information or other information tothe person (e.g., using a vibrator, a screen, a beeper), or otherfunctions.

A wearable body-mountable device 1000 (illustrated in FIG. 10) can beconfigured to detect probes disposed in a wearer's body (e.g., disposedin portions of subsurface vasculature proximate the device 1000) and toexert a magnetic force to collect such probes that include magneticnanoparticles. The term “wearable device,” as used in this disclosure,refers to any device that is capable of being worn at, on or inproximity to a body surface, such as a wrist, ankle, waist, chest, orother body part. In order to take in vivo measurements in a non-invasivemanner from outside of the body, the wearable device may be positionedon a portion of the body where subsurface vasculature or other targetsor elements of the body of the wearer are easily observable, thequalification of which will depend on the type of detection system used.The device may be placed in close proximity to the skin or tissue. Amount 1010, such as a belt, wristband, ankle band, etc. can be providedto mount the device at, on or in proximity to the body surface. Themount 1010 may prevent the wearable device from moving relative to thebody to reduce measurement error and noise. In one example, shown inFIG. 10, the mount 1010, may take the form of a strap or band 1020 thatcan be worn around a part of the body. Further, the mount 1010 may be anadhesive substrate for adhering the wearable device 1000 to the body ofa wearer.

A housing 1030 is disposed on the mount 1010 such that it can bepositioned on the body. A contact surface 1040 of the housing 1030 isintended to be mounted facing to the external body surface. The housing1030 may include a magnetic flux source 1055 for producing a magneticfield sufficient to collect probes that are disposed in the body of thewearer and that include magnetic nanoparticles. The housing 1030 mayadditionally include a sensor 1050 for detecting magnetic fields, light,or other phenomena produced by such probes disposed in the body of thewearer. The housing 1030 could be configured to be water-resistantand/or water-proof.

The magnetic flux source 1055 is configured to produce a magnetic fieldsufficient to collect magnetic nanoparticles disposed proximate to themagnetic flux source 1055 in an environment of interest, e.g., a portionof subsurface vasculature of a wearer. For example, the magnetic fluxsource 1055 could be configured to produce a magnetic field having amagnitude of several hundred Gauss (e.g., greater than approximately 100Gauss) at a distance of approximately 1 centimeter from the contactsurface 1040 (e.g., a distance within which a portion of subsurfacevasculature containing the nanoparticles may be located when the device1000 is mounted to a body). The magnitude of the magnetic field producedby the magnetic flux source 1055 and the dimensions of the magnetic fluxsource 1055 (e.g., the length of the magnetic flux source 1055 in adirection aligned with a direction of the portion of subsurfacevasculature) could be specified such that magneticnanoparticle-containing probes flowing in the body proximate to themagnetic flux source 1055 are collected proximate the magnetic fluxsource 1055.

The magnetic flux source 1055 could be configured to collect such probesand/or to release such collected probes, e.g., to facilitate extractionof the collected probes from the body, to provide a higher-magnitudeoptical, magnetic, or other type of signal for the sensor 1050 todetect, or according to some other application. The magnetic flux source1055 could include one or more electromagnets, permanent magnets, orother magnetic producing elements. Further, the magnetic flux source1055 could be configured and/or operated to change a magnetic fieldproduced by the magnetic flux source 1055, e.g., to reduce a magnitudeof a produced magnetic field that is detected by a magnetometer of thesensor 1050, to reduce an inhomogeneity of the magnetic field proximatea magnetometer of the sensor 1050 that is caused by the magnetic fluxsource 1055, to release collected probes such that the collected probescan be transported, by a blood flow, past the sensor 1030, or accordingto some other application. This could include changing a current appliedto an electromagnet of the magnetic flux source 1055, mechanicallyactuating an electromagnet, permanent magnet, or other flux producingelement of the magnetic flux source 1055, or performing some otheroperation(s).

Note that the magnetic flux source 1055 could be configured to providesome other functionality, e.g., to magnetize the magnetic nanoparticlesof the probes or to polarize the magnetic spins of atomic nuclei suchthat the magnetic field in the environment of such atomic nuclei (e.g.,a magnetic field produced by a magnetized nanoparticle of a probeproximate such atomic nuclei) could be detected (e.g., by themagnetometer 850 detecting time-varying magnetic and/or electromagneticfields produced by such atomic nuclei through nuclear magneticresonance).

The sensor 1050 is configured to detect the presence, number,concentration, location, or other properties of probes as describedelsewhere herein that are located in an environment of interest, e.g., aportion of subsurface vasculature of a wearer. The sensor 1050 couldinclude a light sensor configured to detect an intensity, wavelength,spectral content, polarization, or other properties of light emittedfrom such probes, e.g., light reflected or scattered by a chromophore,dye, or Raman dye of a probe or light fluorescently emitted from afluorescent organic compound, a fluorescent defect in a nanodiamond, orsome other fluorescent element of a probe. Further, sensor 1050 couldinclude one or more light emitters configured to emit light having aspecified intensity, polarization, wavelength, spectral content, or someother specified property in order to optically interrogate the a probe,e.g., to illuminate the probe or to excite a fluorophore of the probe.The sensor 1050 could include a magnetometer that is configured todetect a direction, magnitude, property of change over time, or someother property of the magnetic fields produced by magnetic nanoparticlesor other magnetic elements of a probe. Such a magnetometer could beconfigured to detect time-varying magnetic fields across a specifiedrange of frequencies, e.g., less than several kilohertz (e.g., aspin-exchange relaxation-free atomic magnetometer, a multi-pass scalaratomic magnetometer), at a particular frequency (e.g., a radio-frequencyatomic magnetometer tuned to a frequency of interest, e.g., an expectedfrequency of precession of magnetic spins of atomic nuclei in a magneticfield).

The wearable device 1000 may also include a user interface 1090 viawhich the wearer of the device may receive one or more recommendationsor alerts generated either from a remote server or other remotecomputing device, or from a processor within the device. The alertscould be any indication that can be noticed by the person wearing thewearable device. For example, the alert could include a visual component(e.g., textual or graphical information on a display), an auditorycomponent (e.g., an alarm sound), and/or tactile component (e.g., avibration). Further, the user interface 1090 may include a display 1092where a visual indication of the alert or recommendation may bedisplayed. The display 1092 may further be configured to provide anindication of the presence or properties of one or more detected probesand/or a presence or status of a tumor in the body of the wearer.

Note that example devices herein are configured to be mounted to a wristof a wearer. However, the embodiments described herein could be appliedto other body parts (e.g., an ankle, a thigh, a chest, a forehead, athigh, a finger), or to detect probes in other environments. Further,while the body-mountable device 1000 of FIG. 10 is illustrated as awearable device that is configured to be mounted to an external bodysurface of a person and to be worn by a person, body-mountable devicesas described herein could take other forms. For example, body-mountabledevices could include hand-held devices configured to be manuallymounted to an external body surface of a person (e.g., a wrist surface)such that a sensor of the body-mountable device is proximate to aportion of subsurface vasculature beneath the external body surface.Additionally or alternatively, a body-mountable device may be a desktopor otherwise configured device that a body part can be brought intocontact with (e.g., against which an arm may be positioned) such that asensor of the body-mountable device is proximate to a portion ofsubsurface vasculature beneath an external body surface of the bodypart.

The term “body-mountable device,” as used in this disclosure, refers toany device that is capable of being mounted at, on or in proximity to abody surface and/or a device (e.g., a desktop device) that a body part(e.g., an arm) can be brought into contact with such that a surface ofthe body part is mounted at, or in proximity to, the device. In order totake in vivo measurements in a non-invasive manner from outside of thebody, the body-mountable device may be positioned on a portion of thebody where subsurface vasculature or other targets or elements of thebody of the wearer are easily observable, the qualification of whichwill depend on the type of detection system used. Additionally oralternatively, a portion of the body may be positioned on or within thebody-mountable device such that subsurface vasculature or other targetsor elements of the body of the wearer are easily observable

Body-mountable devices and other embodiments as described herein caninclude a variety of components configured in a variety of ways. Devicesdescribed herein could include electronics including a variety ofdifferent components configured in a variety of ways to enableapplications of the body-mountable device. The electronics could includecontrollers, amplifiers, switches, display drivers, touch sensors,wireless communications chipsets (e.g., Bluetooth radios or other radiotransceivers and associated baseband circuitry to enable wirelesscommunications between the body-mountable device and some othersystem(s)), or other components. The electronics could include acontroller configured to operate one or more magnetic flux sourcesand/or sensors to collect and/or release probe(s) in a portion ofsubsurface vasculature, to detect a light, a magnetic field, or someother physical variable relating to a probe in a portion of subsurfacevasculature, and/or to detect some other properties of a person or toperform some other functions. The controller could include a processorconfigured to execute computer-readable instructions (e.g., programinstructions stored in data storage of the body-mountable device) toenable applications of the body-mountable device. The electronics caninclude additional or alternative components according to an applicationof the body-mountable device.

Body-mountable devices as described herein could include one or moreuser interfaces. A user interface could include a display configured topresent an image to a user and to detect one or more finger presses of auser on the interface. The controller or some other component(s) of theelectronics could operate the user interface to provide information to auser of the device and to enable the user to affect the operation of thebody-mountable device, to determine some property of the body-mountabledevice and/or of a user of the body-mountable device (e.g., a presenceor status of a tumor in the body of a user of the body-mountable deviceand/or some other health state of the wearer), or to provide some otherfunctionality or application to the user. As one example, the user couldpress an indicated region of the user interface to indicate that anamount of probes have been introduced into the body of the user. Otherindicated information, changes in operation of the body-mountabledevice, or other functions and applications of the user interface areanticipated.

Note that the embodiments illustrated in the Figures are illustrativeexamples and not meant to be limiting. Alternative embodiments,including more or fewer components in alternative configurations areanticipated. A body-mountable device could include multiple housings orother such assemblies each containing some set of components to enableapplications of such a body-mountable device. For example, abody-mountable device could include a first housing within which aredisposed one or more magnetic flux sources configured to collectmagnetic nanoparticle-containing probes that are disposed in a user'sbody (e.g., within portions of subsurface vasculature of the user) andone or more sensor configured to detect such collected probes (e.g., todetect such probes while the probes are collected and/or subsequent tothe release of such probes by the magnetic flux source). Thebody-mountable device could additionally include a second housingcontaining a user interface and electronics configured to operate themagnetic flux source(s) and sensor(s) and to present information to andreceive commands from a user of the body-mountable device. Abody-mountable device could be configured to perform a variety offunctions and to enable a variety of applications. Body-mountabledevices could be configured to operate in concert with other devices orsystems; for example, body-mountable devices could include a wirelesscommunication interface configured to transmit data indicative of one ormore properties of the body of a user of the body-mountable device.Other embodiments, operations, configurations, and applications of abody-mountable device as described herein are anticipated.

FIG. 11 is a simplified schematic of a system including one or morebody-mountable devices 1100. The one or more body-mountable devices 1100may be configured to transmit data via a communication interface 1110over one or more communication networks 1120 to a remote server 1130. Inone embodiment, the communication interface 1110 includes a wirelesstransceiver for sending and receiving communications to and from theserver 1130. In further embodiments, the communication interface 1110may include any means for the transfer of data, including both wired andwireless communications. For example, the communication interface mayinclude a universal serial bus (USB) interface or a secure digital (SD)card interface. Communication networks 1120 may be any one of may be oneof: a plain old telephone service (POTS) network, a cellular network, afiber network and a data network. The server 1130 may include any typeof remote computing device or remote cloud computing network. Further,communication network 1120 may include one or more intermediaries,including, for example wherein the body-mountable device 1100 transmitsdata to a mobile phone or other personal computing device, which in turntransmits the data to the server 1130.

In addition to receiving communications from the body-mountable device1100, such as a detected presence, concentration, or amount of a probein a portion of subsurface vasculature, properties (e.g., fluorescenceintensities) of such probes, a rate, frequency, or timing of thepresence of such probes in a portion of subsurface vasculature and/orinformation determined therefrom (e.g., information about the presenceor status of a tumor in the body of a user) or other collectedphysiological properties and data, the server may also be configured togather and/or receive either from the body-mountable device 1100 or fromsome other source, information regarding a user's overall medicalhistory, environmental factors and geographical data. For example, auser account may be established on the server for every user thatcontains the user's medical history. Moreover, in some examples, theserver 1130 may be configured to regularly receive information fromsources of environmental data, such as viral illness or food poisoningoutbreak data from the Centers for Disease Control (CDC) and weather,pollution and allergen data from the National Weather Service. Further,the server may be configured to receive data regarding a user's healthstate from a hospital or physician. Such information may be used in theserver's decision-making process, such as recognizing correlations andin generating clinical protocols.

Additionally, the server may be configured to gather and/or receive thedate, time of day and geographical location of each user of the deviceduring each measurement period. Such information may be used to detectand monitor spatial and temporal spreading of diseases. As such, thebody-mountable device may be configured to determine and/or provide anindication of its own location. For example, a body-mountable device mayinclude a GPS system so that it can include GPS location information(e.g., GPS coordinates) in a communication to the server. As anotherexample, a body-mountable device may use a technique that involvestriangulation (e.g., between base stations in a cellular network) todetermine its location. Other location-determination techniques are alsopossible.

The server may also be configured to make determinations regarding theefficacy of a drug or other treatment based on information regarding thedrugs or other treatments received by a user of the device and, at leastin part, the detection of the presence or other properties of probes inthe vasculature of a user and the indicated health state of the user.From this information, the server may be configured to derive anindication of the effectiveness of the drug or treatment. For example, abody-mountable device may be configured to detect the presence or statusof a tumor by detecting properties of probes that are configured toselectively interact with the tumor and/or cells of the tumor. If a useris prescribed a drug intended to destroy tumor cells, but the serverreceives data from the body-mountable device indicating that, e.g., thenumber of tumor cells in the user's blood has been increasing over acertain number of measurement periods, the server may be configured toderive an indication that the drug is not effective for its intendedpurpose for this user.

Further, some embodiments of the system may include privacy controlswhich may be automatically implemented or controlled by the user of thedevice. For example, where a user's collected probe and health statedata are uploaded to a cloud computing network for trend analysis by aclinician, the data may be treated in one or more ways before it isstored or used, so that personally identifiable information is removed.For example, a user's identity may be treated so that no personallyidentifiable information can be determined for the user, or a user'sgeographic location may be generalized where location information isobtained (such as to a city, ZIP code, or state level), so that aparticular location of a user cannot be determined.

Additionally or alternatively, users of a device may be provided with anopportunity to control whether or how the device collects informationabout the user (e.g., information about a user's medical history, socialactions or activities, profession, a user's preferences, or a user'scurrent location), or to control how such information may be used. Thus,the user may have control over how information is collected about him orher and used by a clinician or physician or other user of the data. Forexample, a user may elect that data, such as health state and detectedprobe data, collected from his or her device may only be used forgenerating an individual baseline and recommendations in response tocollection and comparison of his or her own data and may not be used ingenerating a population baseline or for use in population correlationstudies.

V. EXAMPLE ELECTRONICS PLATFORM FOR A DEVICE

FIG. 12 is a simplified block diagram illustrating the components of adevice 1200, according to an example embodiment. Device 1200 may takethe form of or be similar to one of the wearable and/or body-mountabledevices 130, 800, 900, or 1000 shown in FIGS. 1, 8, 9, and 10. However,device 1200 may also take other forms, such as an ankle, waist, orchest-mounted device. Device 1200 also could take other forms. Forpurposes of illustration, device 1200 is described with reference toprobes 860 in blood vessel 850, as shown in FIG. 8.

In particular, FIG. 12 shows an example of a device 1200 having a sensor1212, a magnetic flux source 1218, a user interface 1220, communicationinterface 1230 for transmitting data to a remote system, and acontroller 1250. The components of the device 1200 may be disposed on amount or on some other structure for mounting the device to enablestable detection of one or more properties (e.g., a magnetic field, alight, or some other physical variable) related to the presence or otherproperties of a probe as described elsewhere herein that is present in abody of a user of the device 1200). For example, the device 1200 couldinclude a structure configured for mounting the device 1220 to anexternal body surface where one or more portions of subsurfacevasculature or other anatomical elements are readily observable.

Controller 1250 may be provided as a computing device that includes oneor more processors 1240. The one or more processors 1240 can beconfigured to execute computer-readable program instructions 1270 thatare stored in the computer readable data storage 1260 and that areexecutable to provide the functionality of a device 1200 describedherein.

The computer readable medium 1260 may include or take the form of one ormore non-transitory, computer-readable storage media that can be read oraccessed by at least one processor 1240. The one or morecomputer-readable storage media can include volatile and/or non-volatilestorage components, such as optical, magnetic, organic or other memoryor disc storage, which can be integrated in whole or in part with atleast one of the one or more processors 1240. In some embodiments, thecomputer readable medium 1260 can be implemented using a single physicaldevice (e.g., one optical, magnetic, organic or other memory or discstorage unit), while in other embodiments, the computer readable medium1260 can be implemented using two or more physical devices.

The sensor 1212 (e.g., a light sensor, a light emitter, a magneticsensor, and/or some other elements) that is configured to detect theprobes 860 in the blood vessel 850 that are proximate the sensor 830.Such detection can include detecting that the probe(s) 860 are presentin the blood vessel 850, determining a number, concentration, or amountof the probes 860 in the blood vessel 850 and/or determining propertiesof the probes 860 in the blood vessel 850.

The sensor 1212 could be configured to detect a variety of physicalproperties in order to detect the presence of the probes 860 and/or todetect one or more properties of individual probes 860 (e.g., a propertyof an individual probe that is indicative of whether the individualprobe has interacted with a tumor) that are located proximate the sensor1212 in a body of a user of the device 1200 (e.g., within a portion ofsubsurface vasculature of the user). This could include detectingphysical variables that are related to fluorophores, chromophores, dyes,Raman dyes, fluorescent nanodiamonds, fluorescent quantum dots, magneticnanoparticles, or other detectable elements of the probes 860.

In examples wherein the probes have a detectable optical property (e.g.,a color, an emission spectrum, an excitation spectrum, an absorptionspectrum, a Stokes shift), the sensor 1212 could be configured to detectsuch an optical property. The sensor 1212 could include a light sensor(e.g., a photodiode, a phototransistor, an avalanche photodiode, a CCDsensor, a camera, a spectrometer) that is configured to detect theintensity, polarization, wavelength, spectral content, degree ofcoherence, or other properties of light received from the probes.Further, the sensor 1212 could include one or more light emittersconfigured to illuminate the probes and/or an environment that couldcontain the probes, e.g., to excite a fluorophore of the probes, tointerrogate a color or absorbance spectrum of the probes, or tointerrogate some other optical property of the probes.

In examples wherein the probes have a detectable magnetic property(e.g., a magnetic moment, a magnetic relaxation time, a coercivity), thesensor 1212 could be configured to detect such a magnetic property. Thesensor 1212 could include a Hall sensor, an atomic optical magnetometer,a multipass atomic magnetometer, a spin exchange relaxation-freemagnetometer, or some other element(s) configured to detect a magnitudeand/or direction of a magnetic field. The sensor 1212 could includeamplifiers, oscillators, ADCs, switches, filters, light emitters, lightdetectors, or other components configured to detect a magnetic fieldusing one or more magnetic-field-sensitive elements of the sensor 1212.For example, the sensor 1212 could be a SERF magnetometer, a multipassscalar atomic magnetometer, a radio-frequency atomic magnetometer, orsome other variety of atomic magnetometer that includes an alkali vaporcell (i.e., an enclosed volume containing a high-pressure,high-temperature vapor that includes alkali metal atoms) and theelectronics could include a heater configured to vaporize the alkalimetal in the vapor cell, a pump laser configured to emit circularlypolarized light into the vapor cell to align the alkali metal atoms, aprobe laser configured to probe the aligned alkali atoms with linearlypolarized light, and a light detector configured to detect the change inorientation of the linearly polarized light that is related to thedetected magnetic field. Other examples of magnetometers and electronicsthereof are anticipated.

The device 1200 could include a bias coil (not shown) that is configuredto produce a bias magnetic field to reduce a background magnetic fieldto which the sensor 1212 (e.g., a magnetometer of the sensor 1212) isexposed and/or to reduce an inhomogeneity of the magnetic field in anenvironment of interest (e.g., to cancel the effects of the Earth'smagnetic field on the sensor 1212, to cancel the effects of the magneticflux source 1218 on the sensor 1212) and/or to provide some otherfunctionality. The bias coil could be driven according to a bias fieldmagnitude determined based on an output of the sensor 1212, an output ofsome other magnetometer (not shown), an output of an accelerometer,gyroscope, or some other sensor, or based on some other consideration.

The magnetic flux source 1218 is configured to produce a magnetic fieldsufficient to collect magnetic nanoparticle-containing probes (e.g., byexerting an attractive magnetic force). The collected probes could becollected in a body (e.g., in a portion of subsurface vasculature) suchthat the presence or some other property of the probes could be detectedby the sensor 1212. Additionally or alternatively, the magnetic fluxsource 1218 could subsequently release such collected probes such thatthe probes can be detected by the sensor 1212 (e.g., by beingtransported by a flow of blood within a portion of subsurfacevasculature from the proximity of the magnetic flux source 1218 to thesensor 1212). The magnetic flux source 1218 could also be configured tomagnetize magnetic nanoparticles of the probes (e.g., such that amagnetometer of the sensor 1212 could detect a magnetic field producedby the magnetized magnetic nanoparticles of the probes) and/or topolarize magnetic spins of atomic nuclei in an environment of interestsuch that the sensor 1212 can detect the presence or other properties ofsuch probes by rotating the polarized magnetic spins of the atomicnuclei and detecting a time-varying magnetic field produced byprecession of the rotated magnetic spins of the atomic nuclei. Themagnetic flux source 1218 could be a permanent magnet and/or anelectromagnet.

Note that a device could include a subset of the elements describedhere, e.g., a device could lack a magnetic flux source and/or some othercombination of elements. Further, a device could include multiple of oneor more illustrated elements. For example, a device could includemultiple sensors 1212 configured to detect a light, a magnetic field, orsome other physical variables at respective multiple different locationsand/or in multiple different directions. In some examples, multipleillustrated elements of the device 1200 could be implemented as the samecomponent and/or share some component(s) in common.

The program instructions 1270 stored on the computer readable medium1260 may include instructions to perform any of the methods describedherein. For instance, in the illustrated embodiment, programinstructions 1270 include a controller module 1272, calculation anddecision module 1274 and an alert module 1276.

The controller module 1272 may include instructions for operating thesensor 1212, magnetic flux source 1218, and/or some other components(e.g., one or more bias coils, pulse emitters, and/or excitation coils)to detect probes (e.g., to detect the presence, location, amount, orother properties) in a portion of subsurface vasculature proximate thesensor 1212 and/or to magnetically collect such probes (e.g., byexerting a magnetic force on magnetic nanoparticles of such probes).

The calculation and decision module(s) 1274 may include instructions foranalyzing data generated by the sensor 1212 to determine informationabout probes in a body (e.g., by detecting the presence of such probesin a portion of subsurface vasculature and/or by detecting properties,of such probes, that are indicative of whether such probes haveinteracted with a tumor) or other information (e.g., health states) of abody of a user of the device 1200, such as a presence or status of atumor in the body of the user. Calculation and decision module 1274 canadditionally include instructions for analyzing the data to determine ifa medical condition or other specified condition is indicated, or otheranalytical processes relating to the environment proximate to the device1200.

In particular, if the probes are configured to be released from a tumorsubsequent to being absorbed into the tumor or to associate with tumorcells and to leave the tumor with associated tumor cells when the tumorcells metastasize, the calculation and decision module(s) 1274 mayinclude instructions for determining the presence of a tumor, a size ofa tumor, a type of a tumor (e.g., if the probes 860 are configured toselectively associate with and/or be released from a particular tumortype), a rate or degree of metastasis of a tumor, or some otherinformation about the presence or status of a tumor. Such determinationscould be made based on an amount of the detected probes, a rate orfrequency at which the probes are detected, and/or a timing of detectionof the probes relative to, e.g., introduction of the probes into thebody.

Additionally or alternatively, if the probes have a property that isindicative of the probes having interacted with a tumor, the calculationand decision module(s) 1274 may include instructions for determining thepresence of a tumor, a size of a tumor, a degree of perfusion of atumor, a type of a tumor (e.g., if the property of the probes isindicative of interaction with a particular tumor type), a property ofthe environment of a tumor (e.g., a pH level in the tumor), a propertyof the interaction between a tumor and the probe(s) (e.g., a duration oftime during which a probe was exposed to a tumor), or some otherinformation about the presence or status of a tumor. Such determinationscould be made based on a measured property of detected probes.

The controller module 1272 can also include instructions for operating auser interface 1220. For example, controller module 1272 may includeinstructions for displaying data collected by the sensor 1212 andanalyzed by the calculation and decision module 1274, or for displayingone or more alerts generated by the alert module 1276. Controller module1272 may include instructions for displaying data related to probes inone or more portions of subsurface vasculature that have been detectedusing the sensor 1212 or some other detected and/or determined healthstate of a user. Further, controller module 1272 may includeinstructions to execute certain functions based on inputs accepted bythe user interface 1220, such as inputs accepted by one or more buttonsdisposed on the user interface.

Communication interface 1230 may also be operated by instructions withinthe controller module 1272, such as instructions for sending and/orreceiving information via a wireless antenna, which may be disposed onor in the device 1200. The communication interface 1230 can optionallyinclude one or more oscillators, mixers, frequency injectors, etc. tomodulate and/or demodulate information on a carrier frequency to betransmitted and/or received by the antenna. In some examples, the device1200 is configured to indicate an output from the processor bymodulating an impedance of the antenna in a manner that is perceivableby a remote server or other remote computing device.

The program instructions of the calculation and decision module 1274may, in some examples, be stored in a computer-readable medium andexecuted by a processor located external to the device 1200. Forexample, the device 1200 could be configured to collect certain data,generated by the sensor 1212, regarding probes in a portion ofsubsurface vasculature in the body of the user and then transmit thedata to a remote server, which may include a mobile device, a personalcomputer, the cloud, or any other remote system, for further processing.The remote server or other device could then use the transmitted data todetermine a presence or status of a tumor in the body of the user.Information about such determinations could then be transmitted to thedevice 1200 and/or could be used in some other way (e.g., could be sentto a physician's computer).

The computer readable medium 1260 may further contain other data orinformation, such as medical and health history of a user of the device1200, that may be useful in determining whether a medical condition orsome other specified condition is indicated (e.g., in determining thepresence or status of a tumor in the body of a user). Further, thecomputer readable medium 1260 may contain data corresponding to certainphysiological parameter baselines, above or below which a medicalcondition is indicated. The baselines may be pre-stored on the computerreadable medium 1260, may be transmitted from a remote source, such as aremote server, or may be generated by the calculation and decisionmodule 1274 itself. The calculation and decision module 1274 may includeinstructions for generating individual baselines for the user of thedevice 1200 based on data collected over a period of time using thesensor 1212. Baselines may also be generated by a remote server andtransmitted to the device 1200 via communication interface 1230. Thecalculation and decision module 1274 may also, upon determining that amedical or other emergency condition is indicated, generate one or morerecommendations for the user of the device 1200 based, at least in part,on consultation of a clinical protocol. Such recommendations mayalternatively be generated by the remote server and transmitted to thedevice 1200.

In some examples, detected information about probes in the vasculatureof a user and/or and information determined therefrom about the presenceor status of tumors in a user's body from a variety of different usersor populations of device users may be used by physicians or cliniciansin monitoring efficacy of a drug or other treatment. For example,high-density, real-time data may be collected from a population ofdevice users who are participating in a clinical study to assess thesafety and efficacy of a developmental drug or therapy. Such data mayalso be used on an individual level to assess a particular user'sresponse to a drug or therapy. Based on this data, a physician orclinician may be able to tailor a drug treatment to suit an individual'sneeds.

In response to a determination by the calculation and decision module1274 that a medical or other specified condition is indicated, the alertmodule 1276 may generate an alert via the user interface 1220. The alertmay include a visual component, such as textual or graphical informationdisplayed on a display, an auditory component (e.g., an alarm sound),and/or tactile component (e.g., a vibration). The textual informationmay include one or more recommendations, such as a recommendation thatthe user of the device contact a medical professional, seek immediatemedical attention, or administer a medication (e.g., a drug to destroyor disable circulating tumor cells).

VI. EXAMPLE METHODS

FIG. 13 is a flowchart of an example method 1300 for detecting thepresence or status of a tumor in a body by detecting, using abody-mountable device mounted to the body, a probe as describedelsewhere herein that is disposed in a portion of subsurface vasculatureof the body. The method 1300 includes introducing the probe into thebody (1310). This could include injecting the probe into the body usinga hypodermic syringe, via a catheter, via an intravenous port, via atransdermal patch or other transdermal delivery means, or via some othermeans for accessing the vasculature. Additionally or alternatively, theprobe could be introduced orally (e.g., in a pill or other ingestiblesubstance) and could be absorbed by the body into the bloodstream.

Introducing the probe into the body (1310) could include introducing theprobe as part of a probe aggregate. Such a probe aggregate could includeone or more instances of the probe bound together and/or to an anchoringelement (e.g., a nanoworm). Such a probe aggregate could be configuredto be absorbed into tissues of the body. In some examples, the probeaggregate could be configured to be absorbed preferentially into tumors(e.g., by leveraging the enhanced permeability and retention effect intumors and/or by including receptors, antibodies, or other elements thatare configured to selectively bind to or otherwise interact with atumor). The probe aggregate could be configured to release the probefrom the tumor into the circulation such that the probe can be detected(e.g., in the portion of subsurface vasculature by the body-mountabledevice). Such a release can occur in response to exposure to the tumorenvironment, e.g., in response to a pH level, an oxygen saturation, aconcentration of lactic acid, the presence of a protease, or some otherfactors present in the tumor that are characteristic of the tumorenvironment.

Additionally or alternatively, introducing the probe into the body(1310) could include introducing a probe that has a property (e.g., afluorescence intensity, a fluorescence emission spectrum) that isindicative of whether the probe has interacted with a tumor. Forinstance, the probe could have a fluorescence intensity that increasesin response to exposure to an environment within a tumor (e.g., due tocleavage of a fluorescence quencher from the probe by a protease that ischaracteristically present in the tumor environment). Such a probe couldtravel, via vasculature of a body, to a tumor and interact with thetumor such that the property of the tumor changes in a manner indicativeof the probe having interacted with the tumor. The probe could thentravel from the tumor to the portion of subsurface vasculature proximateto which the body-mountable device is mounted.

The method 1300 includes mounting the body-mountable device to anexternal body surface (e.g., a skin surface of a wrist) such that thesensor of the body-mountable device is proximate to a portion ofsubsurface vasculature of the body (1320). This could include using astrap, adhesive, or other mounting means to apply a wearablebody-mountable device to the external body surface. In another example,a handheld body-mountable device could be manually placed in contactwith the external body surface. In yet another example, thebody-mountable device could be a desktop device, and an arm or otherbody part could be placed in contact with the body-mountable device suchthat an external body surface of the body part is in contact with thebody-mountable device.

The method 1300 includes detecting, using the sensor of the externalbody surface device, a property of the probe in the portion ofsubsurface vasculature (1330). Detecting a property of the probe (1330)could include detecting the presence of the probe in the portion ofsubsurface vasculature, detecting a number or concentration of the probein the portion of subsurface vasculature, detecting a rate or timing atwhich the probe is present in the portion of subsurface vasculature, ordetecting some other measure of the timing or amount of the presence ofthe probe in the portion of subsurface vasculature. Additionally oralternatively, detecting a property of the probe (1330) could includedetecting a property (e.g., a fluorescence intensity) of the probe(e.g., of an individual probe, or a population of the probe) that isindicative of whether the probe has interacted with a tumor.

Detecting, using the sensor of the external body surface device, aproperty of the probe in the portion of subsurface vasculature (1330)could include detecting a light, a magnetic field, or some otherphysical variable that is related to the probe. For example, the sensorcould be used to detect an intensity, a spectrum, a color, or some otherproperty of light reflected, refracted, fluorescently absorbed andre-emitted, scattered, or otherwise emitted by the probe (e.g., by afluorophore, chromophore, Raman dye, fluorescent nanodiamond, or otherelement of the probe). Additionally or alternatively, the sensor couldbe used to directly or indirectly detect a magnetic field produced bythe probe (e.g., by a nanoparticle of superparamagnetic iron or othermagnetic element of the probe). The sensor could be used to detect someother physical variable that is related to the presence of the probe inthe portion of subsurface vasculature proximate the sensor and/or thatis related to a property of the probe that is indicative of whether theprobe has interacted with a tumor.

The method 1300 additionally includes determining whether a tumor ispresent in the body based on the detected property of the probe in theportion of subsurface vasculature (1340). In particular, if the probe isconfigured to be released from a tumor (e.g., from a probe aggregate orother anchoring element(s)) subsequent to being absorbed into the tumor,the presence of a tumor, a size of a tumor, a type of a tumor (e.g., ifthe probe is configured to selectively be released from a particulartumor type), a rate or degree of metastasis of a tumor, or some otherinformation about the presence or status of a tumor could be determinedbased on an amount of the detected probe, a rate or frequency at whichthe probe is detected, and/or a timing of detection of the proberelative to, e.g., introduction of the probe and/or probe aggregate intothe body. Additionally or alternatively, if the probe has a propertythat is indicative of the probe having interacted with a tumor, thepresence of a tumor, a size of a tumor, a degree of perfusion of atumor, a type of a tumor (e.g., if the property of the probe isindicative of interaction with a particular tumor type), a property ofthe environment of a tumor (e.g., a pH level in the tumor), a propertyof the interaction between a tumor and the probe (e.g., a duration oftime during which the probe was exposed to a tumor), or some otherinformation about the presence or status of a tumor could be determinedbased on the measured property of the probe. Additional or alternativemethods of determining the presence, or other information, of a tumor ina body based on detected properties of a probe in a portion ofsubsurface vasculature are anticipated.

The method 1300 could include additional steps or elements. For example,the method 1300 could include exerting an attractive magnetic field(e.g., from a magnetic flux source of the external body surface device)to collect magnetic nanoparticle-containing probes, e.g., to extract theprobes and/or to increase a magnitude of a signal produced by the probeas detected by the sensor of the external body surface device. Themethod 1300 could include additional or alternative steps.

VII. CONCLUSION

While various aspects and embodiments have been disclosed herein, otheraspects and embodiments will be apparent to those skilled in the art.The various aspects and embodiments disclosed herein are for purposes ofillustration and are not intended to be limiting, with the true scopebeing indicated by the following claims.

Where example embodiments involve information related to a person or adevice of a person, such embodiments may include privacy controls. Suchprivacy controls may include, at least, anonymization of deviceidentifiers, transparency and user controls, including functionalitythat would enable users to modify or delete information relating to theuser's use of a product.

Further, in situations wherein embodiments discussed herein collectpersonal information about users, or make use of personal information,the users may be provided with an opportunity to control whetherprograms or features collect user information (e.g., information about auser's medical history, social network, social actions or activities,profession, a user's preferences, or a user's current location), or tocontrol whether and/or how to receive content from the content serverthat may be more relevant to the user. In addition, certain data may betreated in one or more ways before it is stored or used, so thatpersonally identifiable information is removed. For example, a user'sidentity may be treated so that no personally identifiable informationcan be determined for the user, or a user's geographic location may begeneralized where location information is obtained (such as to a city,ZIP code, or state level), so that a particular location of a usercannot be determined. Thus, the user may have control over howinformation is collected about the user and used by a content server.

What is claimed is:
 1. A body-mountable device comprising: a sensorconfigured to be mounted to an external body surface of a body proximatea portion of subsurface vasculature, wherein the sensor is configured todetect a probe in the portion of subsurface vasculature, wherein theprobe has a property indicative of whether the probe has interacted witha tumor of the body, and wherein the probe is capable of entering thecardiovascular circulation of the body from the tumor of the body; acontroller operably coupled to the sensor, wherein the controllercomprises a computing device programmed to perform controller operationscomprising: operating the sensor to detect the probe, wherein detectingthe probe comprises measuring the property indicative of whether theprobe has interacted with a tumor of the body; and determining whether atumor is present in the body at a location other than the portion ofsubsurface vasculature based on the measured property.
 2. Thebody-mountable device of claim 1, wherein the property indicative ofwhether the probe has interacted with a tumor of the body comprises afluorescence property of a first fluorophore of the probe, wherein thefluorescence property of the first fluorophore is related to whether aquenching moiety of the probe has been cleaved from the probe ordeactivated due to exposure of the probe to a tumor environment.
 3. Thebody-mountable device of claim 2, wherein exposure of the probe to atumor environment comprises exposure of the probe to a pH that ischaracteristic of the tumor environment.
 4. The body-mountable device ofclaim 2, wherein exposure of the probe to a tumor environment comprisesexposure of the probe to a protease that is characteristic of the tumorenvironment.
 5. The body-mountable device of claim 2, wherein thefluorescence property of the first fluorophore comprises a fluorescenceintensity.
 6. The body-mountable device of claim 2, wherein the probecomprises a second fluorophore, wherein the second fluorophore has afluorescence property that is substantially unrelated to whether theprobe has interacted with the tumor of the body, wherein detecting theprobe further comprises measuring the fluorescence property of thesecond fluorophore, and wherein determining whether a tumor is presentin the body comprises comparing the measured fluorescence property ofthe first fluorophore and the measured fluorescence property of thesecond fluorophore.
 7. The body-mountable device of claim 1, wherein theprobe comprises a magnetic nanoparticle, and further comprising: amagnetic flux source configured to be mounted to the external bodysurface, wherein the magnetic flux source is configured to exert anattractive magnetic force on the magnetic nanoparticle to collect theprobe in the portion of subsurface vasculature proximate the sensor. 8.A body-mountable device comprising: a sensor configured to be mounted toan external body surface of a body proximate a portion of subsurfacevasculature, wherein the sensor is configured to detect a probe in theportion of subsurface vasculature, wherein the probe is configured to bereleased by a tumor of the body into the cardiovascular circulation ofthe body after a probe aggregate has been introduced into the body andabsorbed by the tumor, wherein the probe aggregate comprises multipleinstances of the probe linked together; a controller operably coupled tothe sensor, wherein the controller comprises a computing deviceprogrammed to perform controller operations comprising: operating thesensor to detect the probe, wherein detecting the probe comprisesmeasuring an amount of the probe in the portion of subsurfacevasculature; and determining whether a tumor is present in the body at alocation other than the portion of subsurface vasculature based on themeasured amount of the probe in the portion of subsurface vasculature.9. The body-mountable device of claim 8, wherein the probe comprises afluorophore, wherein measuring an amount of the probe in the portion ofsubsurface vasculature comprises detecting an amount of fluorescencelight emitted from the portion of subsurface vasculature by thefluorophore.
 10. The body-mountable device of claim 8, wherein the probeis released from the tumor in response to exposure to a tumorenvironment.
 11. The body-mountable device of claim 10, wherein exposureof the probe to a tumor environment comprises exposure of the probe to apH that is characteristic of the tumor environment.
 12. Thebody-mountable device of claim 10, wherein exposure of the probe to atumor environment comprises exposure of the probe to a protease that ischaracteristic of the tumor environment.
 13. The body-mountable deviceof claim 8, wherein the probe has a property indicative of whether theprobe has interacted with a tumor of the body, wherein detecting theprobe further comprises measuring the property indicative of whether theprobe has interacted with a tumor of the body, and wherein thedetermining whether a tumor is present in the body is further based onthe measured property indicative of whether the probe has interactedwith a tumor of the body.
 14. The body-mountable device of claim 8,wherein the probe comprises a magnetic nanoparticle, and furthercomprising: a magnetic flux source configured to be mounted to theexternal body surface, wherein the magnetic flux source is configured toexert an attractive magnetic force on the magnetic nanoparticle tocollect the probe in the portion of subsurface vasculature proximate thesensor.
 15. A method comprising: introducing a probe into a body,wherein the probe is capable of entering a tumor of the body andsubsequently entering the cardiovascular circulation of the body fromthe tumor of the body; mounting a body-mountable device to an externalbody surface of the body such that a sensor of the body-mountable deviceis proximate a portion of subsurface vasculature of the body; whereinthe sensor is configured to detect a property of the probe in theportion of subsurface vasculature; detecting, using the sensor of thebody-mountable device, the property of the probe in the portion ofsubsurface vasculature; and determining whether a tumor is present inthe body at a location other than the portion of subsurface vasculaturebased on the detected property of the probe in the portion of subsurfacevasculature.
 16. The method of claim 15, wherein introducing a probeinto a body comprises introducing a probe aggregate into the body,wherein the probe is configured to be released by a tumor of the bodyafter the probe aggregate has been introduced into the body and absorbedby the tumor, wherein the probe comprises a fluorophore, wherein theprobe aggregate comprises multiple instances of the probe linkedtogether, wherein detecting a property of the probe comprises measuringan amount of the probe in the portion of subsurface vasculature, andwherein determining whether a tumor is present in the body is based onthe measured amount of the probe in the portion of subsurfacevasculature.
 17. The method of claim 15, wherein the probe has aproperty indicative of whether the probe has interacted with a tumor ofthe body, wherein detecting a property of the probe comprises measuringthe property indicative of whether the probe has interacted with a tumorof the body, and wherein determining whether a tumor is present in thebody is based on the measured property indicative of whether the probehas interacted with a tumor of the body.
 18. The method of claim 17,wherein the property indicative of whether the probe has interacted witha tumor of the body comprises a fluorescence property of a firstfluorophore of the probe, wherein the fluorescence property of the firstfluorophore is related to whether a quenching moiety of the probe hasbeen cleaved from the probe or deactivated due to exposure of the probeto a tumor environment.
 19. The method of claim 18, wherein the probecomprises a second fluorophore, wherein the second fluorophore has afluorescence property that is substantially unrelated to whether theprobe has interacted with the tumor of the body, wherein detecting aproperty of the probe further comprises measuring the fluorescenceproperty of the second fluorophore, and wherein determining whether atumor is present in the body comprises comparing the measuredfluorescence property of the first fluorophore and the measuredfluorescence property of the second fluorophore.
 20. The method of claim15, wherein the probe comprises a magnetic nanoparticle, wherein thebody-mountable device further comprises a magnetic flux sourceconfigured to be mounted to the external body surface, and furthercomprising: exerting, using the magnetic flux source, an attractivemagnetic force on the magnetic nanoparticle to collect the probe in theportion of subsurface vasculature proximate the sensor.